Project 3: Mouse Models of Smoking-related Diseases: What is the Best

点击翻译按钮获取中文摘要

Tobacco smoke has a devastating impact on health, particularly on lung health. It is the most common cause of chronic obstructive lung disease (COPD) and lung cancer. It also has synergistic effects on numerous other lung diseases, including interstitial lung disease and pneumonia. Most mouse models oftobacco smokerelated lung disease expose mouse strains to tobacco smoke. This model usually results in mild-to-moderate emphysema, but little or no evidence ofthe chronic bronchitis, which is a large component of COPD in humans. Our aim is to establish a model oftobacco smoke-induced lung injury that mimics that found in humans. This work will address the FDA CPT research interest, "Adverse Health Consequences". The goal ofthis project is to determine what animal models can be validated to establish standard toxicity changes and what magnitude observed within in vivo assays correlates with change in human health outcome (point 31). As described in Project 1, smoke exposure leads to decreased activity of CFTR, resulting in absorption of water from airway liquid, dehydration of mucus, and poor mucociliary clearance. Transgenic mice overexpressing Scnnib, the gene which codes forthe epithelial Na* chanriel subunit (pENaC), in the epithelial cells ofthe airways mimic this aspect oftobacco smoke, showing mucus cell metaplasia, mucus hypersecretion and obstruction, neutrophilic inflammation, large foamy macrophages, and increased numbers of lymphocytes in both the lumen and the walls ofthe ainways. These mice also show evidence of an MMP-12-dependent emphysematous component to the injury. Thus, the lungs of these mice develop pathology that mimics changes found in COPD patients, highlighting the striking effects of airway dehydration. However, these mice are missing all other effects oftobacco smoke, which are likely to be many due to numerous components of tobacco smoke. We are modeling tobacco smoke exposure in humans by exposing Scnn1b-tg mice to prolonged (6 month) tobacco smoke exposure. Our studies to date suggest that this model mimics the human injury more closely than mouse models to date. In particular, gene expression analysis suggests that smoke exposure in Scnnlb-ig mice results in more similarities to human disease in both detoxification pathways and in immune regulatory pathways. Other similarities to date include changes in mucins within the airways and the presence of large numbers of vesicular exosomes. Thus, we propose to test the hypothesis that smoke exposure in Scnn1b-tg mice is an excellent model of human disease and can be used more effectively than either wild type (WT) mice or other mouse models of COPD to study particular components of smoke or to compare tobacco products or substitutes.